PROJECT SUMMARY (Jason Bates) Amide bonds are one of the most common functional groups present in pharmaceuticals, and reactions to form them are among the most frequently practiced by medicinal chemists. While stoichiometric methods of amide synthesis involve significant waste, current catalytic methods are limited either in their scope and chemoselectivity, use of precious metals, high temperature or pressure conditions, or often some combination of these drawbacks. Aerobic oxidative coupling of amines with alcohols is a promising route in terms of its atom economy and typically mild conditions, but heterogeneous catalysts based on earth-abundant metals have not been identified for this chemistry. Heterogeneous catalysis opens new opportunities in pharmaceutical synthesis for unique active site configurations on solids, minimized waste via ease of separation and recycling, and adaptability for flow-based production. This proposal describes the development of oxidative amide coupling strategies based on metals in nitrogen-doped carbon solids using dioxygen as oxidant. A comprehensive screening approach will be employed to identify optimal catalysts and reaction conditions for representative model substrates encompassing a range of alcohols and amines. The methodology will be applied to synthesize target pharmaceutically relevant molecules including those bearing challenging functional groups to probe the extent of chemoselectivity, and the sensitivity to stereocenters will also be explored. Detailed kinetic and mechanistic studies, Hammett studies, and H/D kinetic isotope effect experiments are proposed to elucidate the elementary steps, resting states, and rate-controlling processes involved in aerobic oxidations on the heterogeneous catalysts studied. Fundamental insights into the factors that lead to preferential alcohol activation and ultimately amide coupling can be intuitively extended to other chemistries that share similar transition states. Mechanistic investigations will be extended to probe the role of co-catalytic nitroxyl radicals that accelerate oxidation rates. Design rules for the selection of co-catalytic nitroxyls with heterogeneous catalysts will be developed, which represent a modular strategy for altering reactivity and chemoselectivity without changing any other experimental conditions. Mechanism-based intuition also suggests the rational design of new catalytic solid architectures to promote amide coupling. Nitrogen-doped carbon materials with metals confined within binding pockets of molecular dimension will be developed in order to stabilize reactive intermediates in the catalytic cycle, and to effect chemoselective catalysis based on size-exclusion. A second class of heterogeneous catalysts with well-defined ligand spheres will be synthesized to shed light on the site requirements and role of support functional groups in oxidative amide coupling catalysis. The development of heterogeneously catalyzed oxidative amide coupling reactions and fundamental understanding of their mechanisms and the active sites where they occur will enable atom-efficient synthesis of amide bonds in diverse pharmaceutical molecules that contribute to positive health outcomes, and facilitate development of related heterogeneous catalytic systems for diverse chemistries.